The avermectins (previously referred to as C-076 compounds) are a series of compounds produced by fermentation of avermectin producing strains of Streptomyces avermitilis and derivatives thereof. The morphological characteristics of the culture are completely described in U.S. Pat. No. 4,310,519. The production, isolation, and structure determination of the avermectins are fully described in Albers-Schonberg et al., J. Am. Chem. Soc. 1981, 103, 4216-4221 and references cited therein. The conversion of natural avermectin B1 to 22,23-dihydro-avermectin B1, the potent broad spectrum anthelminthic agent known as ivermectin, has also been described in the literature (Chabala et al., J. Med. Chem. 1980, 23, 1134-1136). The naturally occurring avermectins and the instant derivatives thereof have a very high degree of anthelminthic and anti-parasitic activity.
The naturally occurring avermectins are a series of macrocyclic lactones which are substituted at position 13 with a disaccharide consisting of two oleandrose residues. The preparation and properties of synthetic avermectin aglycones in which the disaccharide moiety has been removed leaving a free hydroxyl group at position 13 have been described by Mrozik et al., J. Org. Chem. 1982, 47, 489-492 and by Chabala et al., J. Med. Chem. 1980, 23, 1134-1136. The natural compounds have the following general structure: ##STR1## wherein the broken line at the 22,23-position indicates a single or double bond and;
R.sub.1 is hydroxy and is present only when said broken line indicates a single bond; PA1 R.sub.2 is isopropyl or sec-butyl; and PA1 R.sub.3 is methoxy or hydroxy. PA1 R.sup.1 is: PA1 R.sup.2 is: PA1 Z is: PA1 R.sup.3 is: PA1 R.sup.5 and R.sup.5A are independently: PA1 R.sup.6 is: PA1 R.sup.4 is: PA1 X is: PA1 R.sup.3 is F; PA1 R.sup.4 is F; PA1 Y is: PA1 R.sup.1 is: PA1 R.sup.2 is: PA1 Z is: PA1 X is: PA1 R.sup.3 is F PA1 R.sup.4 is F PA1 Y is: PA1 R.sup.1 is --CH.sub.3 ; PA1 R.sup.2 is: PA1 Z is : PA1 X is .dbd.CH--(10, 11 double bond). PA1 Y is --CF.sub.2 --; PA1 R.sup.1 is: PA1 R.sup.2 is: PA1 Z is : PA1 R.sup.3 is: PA1 R.sup.4 is: PA1 X is: PA1 Y is --CF.sub.2 --; PA1 R.sup.1 is --CH.sub.3 --; PA1 R.sup.2 is: PA1 Z is: PA1 R.sup.3 is: PA1 R.sup.4 is --F--; PA1 X is .dbd.CH--(10, 11 double bond). PA1 R.sup.3 is: ##STR5## A is --CF.sub.2 --; R.sup.4 is --H; PA1 Y is: PA1 R.sup.1 is --CH.sub.3 ; PA1 R.sup.2 is: PA1 Z is: PA1 X is: PA1 R.sup.3 is: ##STR6## Wherein: A is --CF.sub.2 --; PA1 R.sup.4 is --H; PA1 Y is: PA1 R.sup.1 is --CH.sub.3 ; PA1 R.sup.2 is: PA1 Z is: PA1 X is .dbd.CH--(10, 11 double bond).
There are eight major natural avermectin compounds, designated A1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b. These designations are based on the structure of the individual compounds as shown in the following table (referring to the foregoing structural formula).
______________________________________ Compound 22,23-bond R.sub.1 R.sub.2 R.sub.3 ______________________________________ A1a double bond -- sec-butyl --OCH.sub.3 A1b double bond -- isopropyl --OCH.sub.3 A2a single bond --OH sec-butyl --OCH.sub.3 A2b single bond --OH isopropyl --OCH.sub.3 B1a double bond -- sec-butyl --OH B1b double bond -- isopropyl --OH B2a single bond --OH sec-butyl --OH B2b single bond --OH isopropyl --OH ______________________________________
The avermectins are generally isolated as mixtures of the a and b components (typically .gtoreq.180% a and .ltoreq.120% b). Such compounds differ only in the nature of the R.sub.2 substituent and this minor structural difference has been found to have very little effect on the chemical reactivity or biological activity of the compounds. Thus although the a and b components can be separated from each other by chromatography this is not necessary and hence is not normally done. The presence of a mixture of a and b components may be indicated by dropping the a or b from the designation of the compound. A mixture of avermectin B1a and avermectin B1b is thus referred to as avermectin B1. Alternatively a slash(/) is inserted between the compound designations to indicate a mixture such as in "B1a/B1b".
The above structural formula is shown without a definitive stereochemistry at certain positions and with a defined stereochemistry at other positions. However, during the course of the synthetic procedures used to prepare such compounds, or using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers. In particular, the stereoisomers at the 13- and 23-positions may be oriented either .alpha.- or .beta.-representing such groups being below or above the general plane of the molecule, respectively. In each such case, and at other positions in the molecule, both the .alpha.- and .beta.- configurations are intended to be included within the ambit of this invention.
A related family of natural products is known as the milbemycins. The milbemycins have the same macrocyclic ring structure as the avermectins but have no substitution at position 13 and have a methyl or ethyl group at position 25 (R.sub.2 =methyl or ethyl rather than isopropyl or sec-butyl as in the avermectins). The milbemycins and the fermentation conditions used to prepare them are described in U.S. Pat. No. 3,950,360. Closely related 13-deoxy-avermectin aglycones are prepared by chemical modification of the natural avermectins and have been described in U.S. Pat. Nos. 4,171,134 and 4,173,571.
Recently a number of related compounds have been described in European Patent Application EPO 170,006 and U.K. application 2,166,436 (see also Carter et al., J. Antibiotics 1988, 41, 519-529). These compounds are essentially 13-deoxy-avermectin aglycones in which the R.sub.2 side chain contains a double bond and, in some cases, includes additional carbon atoms.